Novel approaches for the early detection of renal cancer are urgently needed. Adult sporadic cancers are known to arise through the accumulation of multiple clonal genetic or epigenetic alterations which can be used as targets for the detection of neoplastic cells in bodily fluids that surround or drain from an organ. Since most renal tumors arise from the tubular epithelium and the renal parenchyma itself is in close proximity to the urinary collecting system, we hypothesized that urine from patients with renal cancer may contain shed neoplastic cells or DNA amenable to analysis. Using the sensitive methylation specific PCR (MSP) we have established that cancer specific hypermethylation of a panel of normally unmethylated tumor suppressor and cancer genes is frequent and can be detected in a simple voided urine from patients with early renal cancer. We have demonstrated for the first time that highly sensitive and specific MSP-based detection of renal cancer in urine is feasible. Our specific goals are 1) to construct a hypermethylation progression model and profile for early renal cancer by determining the frequency and timing of hypermethylation of the panel of cancer genes in defined pathological stages, 2) to validate the MSP assay for detection of renal cancer cell DNA in urine from 100 organ-confined renal cancers and to examine specificity in urine from 100 normal and benign controls, 3) to elucidate the methylome profile of early renal cancer and 4) to examine the diagnostic utility of proteomic based detection of early renal cancer. A progression model of early renal cancer will identify the most useful markers for early diagnosis and verify that hypermethylation is a valid detection target. Validation of a simple, non-invasive test for renal cancer would be of immense benefit towards the earlier diagnosis, and thereby cure, of this disease. The methylome profile will provide signatures for early renal cancer and an optimal detection panel of methylated genes. Serum proteomics based detection can be compared with methylation-based technology. Our long range goal is to make this molecular detection test a clinical reality. We have preliminary evidence which indicates that a sensitive and specific molecular test providing diagnosis of early renal cancer is feasible from a simple urine specimen. We will test this further.